1. Field of the Invention
The present invention relates to a tumor peptide marker and application thereof, particularly a tumor peptide for applying in targeted delivery of chemotherapeutic drugs specifically to nasopharyngeal carcinoma (NPC) cells.
2. The Prior Arts
Nasopharyngeal carcinoma (NPC) occurs in high incidence among Chinese living in South China, Taiwan and Singapore. Genetic and environmental factors are important in the development of NPC. The etiological factors have not been clearly identified yet, but factors such as the habits of eating salted fish, Chinese herbs and long term exposure to the sulphuric acid vapor have been related to NPC induction. In addition, Epstein-Barr (EB) virus has also been found to be closely associated with NPC.
The medical treatments for NPC, such as radiotherapy, surgical removal and chemotherapy have been applied for more than 30 years. The 5 year survival rate has been improved to be more than 90% in the localized NPC cases in some medical centers. However, the survival rate drops to below 50% in advanced stage NPC patients. Efforts such as high dose chemotherapy plus bone marrow stem cell injection and targeting therapy are employed to improve the effectiveness of chemotherapy.
Most cancer cells and their normal host cells usually share many common features which makes the former cells lack of molecular targets. Many of chemotherapy's most severe toxic effects stem directly from their non-selective nature; most available compounds that inhibit tumor cell growth also inhibit the growth of normal cells. Therefore, chemotherapeutics with high toxicity including doxorubicin could not be regularly applied in cancer therapy because of owing selectivity for cancer cells which resulted increased toxicities against normal tissues such as bone marrow, gastrointestinal tract and hair follicles. Side effects that occur as a result of toxicities to normal tissues mean that anticancer chemotherapeutic drugs are often given at sub-optimal doses, resulting in the eventual failure of therapy; often accompanied by the development of drug resistance and metastatic disease. Therefore, ligand-targeted therapy with drugs that target the molecular differences between tumor and normal cells promise to be less toxic and more effective than our current drugs. Such advances are leading to new applications in cancer therapy.
Conventional chemotherapy is limited by the toxicity toward normal cells. It will be greatly improved if drugs were delivered to cancer cells directly and kept away from sensitive normal cells. Generally small-molecule compounds contain large volumes of distribution which spread into the whole body and are easily accumulated in normal tissues (Speth et al., 1988). This may result in the eventual failure of chemotherapy accompanied with the development of drug resistance or metastatic disease.
Through encapsulation of drugs in a macromolecular carrier, such as a liposome, the volume of distribution is significantly reduced and the local concentration of drug in the tumor area is increased (Drummond et al., 1999), resulting in decreases of dosage and nonspecific toxicities and increase the effectiveness of drug dosage.
Liposomes are aqueous compartments enclosed by a lipid bilayer which protect the drugs from being metabolized and inactivated in plasma. Due to the size limitations in the transportation of large molecules or carriers across healthy endothelium, the drugs encapsulated in liposomes are accumulated to a reduced extent in healthy tissues (Mayer et al., 1989; Working et al., 1994). Liposomes contain a lipid membrane that is relatively impermeable to both amphipathic and highly water-soluble molecules at physiological temperatures (37° C.). This feature is important in drug stability either during storage or in plasma. The internal aqueous space of liposomes can also be used to entrap a variety of chemotherapeutic drugs like doxorubicin or diagnostic dyes (Drummond et al., 1999).
Many small molecules can be delivered to the target sites with targeted immunoliposomes recently (Ahmad et al., 1993; Martin et al., 1982; Papahadjopoulos et al., 1991). The formulations of liposomes in early stage were removed rapidly from blood circulation by the reticuloendothelial system, thus preventing the liposomes from reaching the target sites. Liposomes containing various lipid derivatives of polyethylene glycol (PEG) have resulted in improved circulation time and tumor localization (Papahadjopoulos et al., 1991).
Though the abovementioned approaches in cancer targeting therapy decrease the toxicity toward normal tissues more or less in chemotherapy, the clinical effects are still not ideal. Currently, an important advance in cancer targeting therapy is to identify peptide markers and tumor-associated ligands that afford tumor detection and drug limited toxicity.